ABSTRACT: Project 4. Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma and has a highly variable clinical course. Asymptomatic and low-tumor burden patients can initially be managed by observation or rituximab-monotherapy, while symptomatic and high-tumor burden patients are typically managed at diagnosis with immunochemotherapy (IC) as standard of care. We have shown that IC-treated FL patients who achieve event-free (i.e., no disease progression or re-treatment) status at 24 months after diagnosis (EFS24) have the subsequent life expectancy of the background age and sex matched general population, while those who fail to achieve EFS24 have aggressive disease with poor outcomes. One of the highest priorities for the new NCI-driven paradigm for progress in FL is to address early events in FL including understanding the underlying biology, identifying prognostic and predictive markers, and ultimately developing new therapeutic targets and management strategies for these patients. We hypothesize that a novel combination of germline (host) and somatic (tumor) genomic biomarkers, tumor gene expression, and clinical factors, can improve our ability to predict at diagnosis which IC-treated FL patients will have an early clinical failure, defined as failure to achieve EFS24. To test this hypothesis, we propose to identify, validate and clinically translate germline genetic biomarkers (Aim 1), somatic tumor genomic biomarkers (Aim 2), and gene expression signatures (Aim 3) for failure to achieve EFS24 in IC-treated FL and then develop and validate a novel integrative model (Aim 4) that combines clinical prognostic factors with the biomarkers identified from Aims 1-3. To address these aims, we have assembled an outstanding interdisciplinary team with extensive expertise in the proposed studies. The study leverages the established resources of the Lymphoma SPORE, our horizontal collaborations (LLMPP, SWOG, LYSA), and our leadership in the Lymphoma Epidemiology of Outcomes (LEO) cohort. Our innovative population science project will be the first to comprehensively discover and validate germline genetic, tumor genomic, and gene expression biomarkers for failure to achieve EFS24. We have designed studies that have high internal validity, with a focus on use of large patient cohorts with high quality biospecimens, clinical and outcome data; extensive quality control in biologic sample handling and assays; and multi-stage studies with external validation of results, including use of a geographically and racially/ethnically diverse sample of IC-treated FL patients from the LEO cohort study, which also enhances the generalizability of our results. Our comprehensive approach of discovery-validation and clinical translation should yield a reliable, multiparameter, prognostic model, with potential for major impact on the management of IC-treated FL patients with the ultimate goal of accurate, personalized patient management as well as new insights into lymphoma biology that can also aid in identification of therapeutic targets.